Semicarbazone compound preparation method and application in biomedicine

Abstract

The present invention provides a semicarbazone compound preparation method and application in biomedicine. The compound is a compound of formula (I) or an enantiomer, a diastereomer, a raceme, a pharmaceutically acceptable salt, a crystalline hydrate or a solvate thereof. The compound has the formula shown in the description, wherein X is sulfur or oxygen; R1 and R2 are separately and independently hydrogen and alkyl containing 1-3 carbon atoms or N=CHR 5, wherein R5 is optionally substituted aryl or optionally substituted alkyl; R3 and R4 are separately and independently hydrogen or alkyl containing 1-3 carbon atoms or substituents selected from formulas III, III, IV, and V shown in the description, wherein X1 is sulfur or oxygen. Y, Y1 and Y2 are separately and independently at least one of hydrogen, alkyl containing 1-3 carbon atoms, halogen, hydroxy, methoxy, amino, sulfonic acid group, nitro, carboxyl, thiol, methylamino, ethylamino, dimethylamino or diethylamino; and Z1 is hydrogen, alkyl containing 1-3 carbon atoms, halogen, hydroxy, amino, methylamino, ethylamino, dimethylamino or diethylamino. The semicarbazone compound is applicable to related diseases caused by copper metabolic dysfunction.

Description

technical field [0001] The present invention relates to the field of chemistry, specifically, the present invention relates to compounds and preparation methods and applications thereof, and more particularly, the present invention relates to compounds represented by formula I and derivatives thereof, preparation methods and applications thereof. Background technique [0002] Copper-zinc superoxide dismutase (SOD1) is a metalloenzyme with important antioxidant functions in organisms. The metal prosthetic groups zinc and copper determine the structure and activity of the enzyme. Cu 2+ directly involved in the catalytic reaction, while Zn 2+ maintains the conformation of the enzyme and does not directly participate in the reaction; but Cu 2+ and Zn 2+ It is indispensable for the stability of the structure of SOD1. After the chelating agent interacts with SOD1, apo-SOD1 is formed, and its structure changes, and excess Zn is added. 2+ can restore the structure of SOD1, but C...

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Problems solved by technology

However, it was also found that MoS 4 2- The inhibition of SOD1 activity by DDC and DDC lacks specificity, and has a more obvious effect on the activity of other intracellular copper-containing proteins, such as MoS 4 2- It can significantly inhibit the activity of cytochrome c oxidase while inhibiting the activity of SOD1

In addition, MoS 4 2- The chelating ability of DDC and DDC to copper ions is too strong, which will destroy the homeostasis of intracellular copper ions. The copper complexes formed by chelation are not easy to metabolize in the body, and the enrichment in the body causes secondary damage.

[0008] The chelating agents that have been reported as SOD1 activity inhibitors are only the above two examples. Although they can effectively inhibit SOD1 activity, they have obvious defects: (1) negatively charged, unable to cross the blood-brain barrier and cell membrane; (2) Lack of specificity, resulting in the activity of other copper-containing proteins in the cell being affected to varying degrees

Although the existing chelating agent-like SOD1 inhibitors can inhibit its enzyme activity, the defects are also very obvious, and even become a technical bottleneck in the later stage of drug development.

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